Method for the production of benzodiazepine derivatives

ABSTRACT

COMPOUNDS OF THE FORMULA   2-(O=),5-(C6H5-),7-O2N-1,2-DIHYDRO-3H-1,4-BENZODIAZEPINE   WHEREIN PH REPRESENTS A SUBSTITUTED OR UNSUBSTITUTED PHENYL GROUP ARE PREPARED BY REACTING A COMPOUND OF THE FORMULA   4-NO2,2-(C6H5-CO-),1-NH2-BENZENE   WITH A COMPOUND OF THE FORMULA   XCH2C(OR)3   WHEREIN X REPRESENTS A HALOGEN ATOM AND R REPRESENTS A LOWER ALKYL GROUP, TO PRODUCE A COMPOUND OF THE FORMULA   4-NO2,2-(C6H5-CO-),1-(X-CH2-C(-O-R)=N-)BENZENE   REACTING SAID COMPOUND III WITH AMMONIA TO PRODUCE A COMPOUND OF THE FORMULA   4-NO2,2-(R-OOC-CH2-N=C(-C6H5)-),1-NH2-BENZENE   AND SUBJECTING SAID COMPUND II TO A RING-CLOSURE REACTION. COMPOUNDS I ARE USEFUL AS TRANQUILIZER OR HYPNOTIC AGENTS OR AS INTERMEDIATES FOR OTHER MEDICINES. COMPOUNDS III ARE NOVEL PRODUCTS.

United States Patent 3,746,701 METHOD FOR THE PRODUCTION OF BENZO-DIAZEPINE DERIVATIVES Hiroyuki Tawada, Kyoto, Hideaki Natsugari, Osaka,and Kanji Meguro and Yutaka Kuwada, Hyogo, Japan, assiguors to TakedaChemical Industries, Ltd., Osaka, Japan No Drawing. Filed July 27, 1971,Ser. No. 166,627 Claims priority, application Japan, Aug. 1, 1970,45/67,447, 45/ 67,448 Int. Cl. C07d 53/06 U.S. Cl. 260239.3 D 12 ClaimsABSTRACT OF THE DISCLOSURE Compounds of the formula Ph wherein Phrepresents a substituted or unsubstituted phenyl group are prepared byreacting a compound of the formula OzN- with a compound of the formulaXCH C(OR) (VI) wherein X represents a halogen atom and R represents alower alkyl group, to produce a compound of the formula l h (III)reacting said Compound III with ammonia to produce a compound of theformula h (II) and subjecting said Compound II to a ring-closurereaction. Compounds I are useful as tranquilizer or hypnotic agents oras intermediates for other medicines. Compounds III are novel products.

The present invention relates to a method for the production ofbenzodiazepine derivatives, and more particularly to a novel andindustrially feasible method for the production of benzodiazepinederivatives of the following general Formula I, which are useful asmedicines, such as effective tranquilizers, hypnotics, or intermediatesfor other various kinds of medicines 3,746,701 Patented July 17, 1973ice wherein Ph stands for a substituted or unsubstituted phenyl group.The invention also provides novel compounds which are useful, interalia, as intermediates in the production of Compounds I.

The method of the present invention, by which the above object CompoundsI can be produced, comprises reacting a compound of the general FormulaV wherein Ph has the same meaning as above with a compound of thegeneral Formula IV wherein X stands for a halogen atom, and R stands fora lower alkyl group to give a compound of the general Formula III I Ph(III) wherein Ph, R and X have the same meaning as above, reacting thecompound of the general Formula III with ammonia to give a compound ofthe general Formula II Ph (II) wherein Ph and R have the same meaning asabove, and finally subjecting the compound of the general Formula II toring-closure reaction to give the object Compound I.

Reactions involved in the present method are shown in the followingscheme:

wherein Ph, R and X have the same meaning as above.

There have been reported a number of methods for the production of theCompounds 1. However, the known methods for the production of theCompounds I are not very satisfactory from an industrial point of viewsuch as yield, handling of intermediates and complexity of theprocesses.

Under these circumstances, the present inventors have made extensivestudies for developing novel and advantageous routes for the productionof the Compounds 1.

As the result of the studies, the present inventors have found that anunexpected intramolecular rearrangement occurs when a compound of theaforementioned Formula III, novel compounds synthesized for the firsttime by the present inventors, is reacted with ammonia. As the result,the Compound H is produced in a high yield.

This finding is quite unexpected and beyond the state of the art at thepresent stage, since the most reasonable assumption from the presentstate of the art is that the reaction of the Compound III with ammoniawould give the compound of the general Formula VI O N o=o l h (VI)wherein Ph and R have the same meaning as above, and such rearrangementas involved in the present method or its analogous rearrangement hasnever been reported so far as the present inventors are aware.

Thus, the reaction of Step [B] of the present invention can be concludedas quite a novel and unique one, because of the unexpected rearrangementinvolved therein.

Further studies on the Compound II has reached a finding that theCompound II is easily susceptible to ringclosure reaction to give theCompound I in a high yield.

Moreover, the aforementioned Step [A], Step [B] and Step [C] cancontinuously be conducted without separation or purification of therespective intermediates.

The present invention has been accomplished on the basis of thesefindings. Thus, according to the present method, the object compounds ofthe general Formula I can be easily produced in a high yield by simpleproc esses, and therefore the present method is remarkably feasible,effective and advantageous from an industrial point of view.

Namely, a principal and essential object of the present invention is toprovide a novel and industrially feasible method for the production ofthe Compounds I, and this object can be attained by the method describedin detail hereinafter.

In the above general formulas, where the symbol Ph is a substitutedphenyl group, the substituent includes, for example, a halogen atom(e.g. chlorine, bromine, iodine, fluorine), a hydroxy group, a nitrogroup, a trifiuoromethyl group, a lower alkyl group (e.g. methyl, ethyl,propyl, isopropyl, butyl) and a lower alkoxy group (e.g. methoxy,ethoxy, propoxy). One or more of these substituents, which are same ordifferent, may occupy optional position(s) of the phenyl nucleus. Thehalogen atom represented by the symbol X includes, for example,chlorine, bromine and iodine. As the lower alkyl group represented bythe symbol R, one having 1 to 4 carbon atoms is preferred, whichincludes methyl, ethyl, propyl, isopropyl, butyl and isobutyl.

The reaction of Step [A] is carried out by reacting a Compound V with aCompound IV. The amount of a Compound IV is at least one mole, morepreferably about 1.5 to about 3 moles per mole of a Compound V. Thereaction proceeds even in the absence of any solvent or catalyst, butuse of a suitable solvent and/or a catalyst is preferable. Suitablesolvents include, for example, benzene, toluene, xylene, carbontetrachloride, chloroform, methylene chloride and a mixture of two ormore thereof, and the catalyst preferably used includes acidic compoundssuch as organic acids (e.g. acetic acid, p-toluenesulfonic acid) andinorganic acids (e.g. hydrochloric acid, and sulfuric acid). The amountof the catalyst is generally about 1 to about 8 moles, more preferablyabout 2 to about 3 moles per mole of a Compound V. The reaction isgenerally conducted ranging from room temperature to boiling point ofthe solvent used.

In case where the Compound III thus produced is that wherein the halogenatom represented by the symbol X is chlorine or bromine, it ispreferable for enhancing the reactivity with ammonia to convert the sameinto a Compound III wherein X is iodine by treatment with an alkalimetal salt of hydroiodic acid (e.g. potassium iodide and sodium iodide)in a suitable solvent such as acetone, alcohols (e.g. methyl alcohol andethyl alcohol).

Thus produced Compound III may be, if necessary, isolated after aconventional means (e.g. extraction and distillation), but the reactionmixture, as it is, of Step [A] can be used as a starting material of thenext reaction Step [B].

The reaction of Step [B] is carried out by reacting a Compound III withammonia. Ammonia usable in the present reaction may be any of liquidammonia, gaseous ammonia and an aqueous solution of ammonia, among whichliquid ammonia is most preferable. The amount of ammonia is generally anexcess molar amount.

The reaction may he preferably conducted in a suitable solvent or in anexcess amount of liquid ammonia which acts also as a solvent, at roomtemperature or below, if necessary, in a sealed vessel. Typical examplesof the solvent are alcohols (e.g., methyl alcohol and ethyl alcohol),halogenomethane (e.g., dichloromethane and chloroform), ethyl acetate,ether, benzene, dimethylformamide, a mixture of two or more thereof, anda mixture with water.

The reaction product of Step [B] can be identified as the compound ofthe general Formula II by the data of infrared absorption spectrum,nuclear magnetic resonance spectrum and elementary analysis. In respectto the Compound II, two geometrical isomers, namely a syn-form shown bythe general Formula II-a and an anti-form shown by the general FormulaII-b exist P h (II-a) 1 1: (IL-b) wherein Ph and R have the same meaningas above.

But one of the isomers is preferentially formed in the reaction of Step[B]. This isomer is identified as syn-form II-a, which is a preferableform for ring-closure reaction in the next Step [C]. The syn-form caneasily be converted into the anti-form by heating in a suitable solventsuch as benzene, toluene, and xylene, generally at the boiling pointthereof. This isomerization gradually proceeds even at room temperature.

These two geometrical isomers can be discriminated from each other bythe data of nuclear magnetic resonance spectrum (in DMSO-d.,):

syn-form of the general Formula II-a: 6:6.33 p.p.m.

(due to -NH anti-form of the general Formula II-bz 6:8.95 p.p.m.

(due to -NH:)

Judging from these data of nuclear magnetic resonance spectrum, it issupposed that the protons due to NH of anti-form appear at lower fieldthan the protons due to --NH of syn-form, because of an intramolecularhydrogen bond in the anti-form.

As a starting material of the next reaction of Step [C], either of thesetwo geometrical isomers or a mixture thereof may be used. The reactionmixture, as it is, of Step [B] can be used as a starting material of thenext Step [C] without any procedure for isolation or purification.

The reaction of Step [C] is carried out by subjecting a Compound II toring-closure reaction. The ring-closure reaction may be conducted bytreating a Compound II with an acid or a basic substance such as animidazole derivative, an alkali metal alcoholate and an alkali metalhydroxide at room temperature or under heating, if necessary. As thealkali metal alcoholate, methylate or ethylate of potassium or sodium ispreferable, and as the alkali metal hydroxide, potassium hydroxide andsodium hydroxide is preferable.

The amount of the alkali metal alcoholates or alkali metal hydroxides isgenerally about 1 to about 1.5 moles per moleof a Compound II.

Where the alkali metal compound is employed, the reaction of Step [C] ispreferably conducted at room temperature, in a suitable solvent such asalcohols (e.g. methyl alcohol, ethyl alcohol, propyl alcohol andisopropyl alcohol).

As mentioned before, syn-form of a Compound II is preferentiallyproduced in Step [B]. Thus Step C] proceeds smoothly under these mildconditions.

The imidazole derivatives include, for example, imidazole,2-methylimidazole and 2-ethylimidazole. The amount of the imidazolederivatives is generally about 1 to about 5 moles per mole of a CompoundII. Where the imidazole derivative is employed, the reaction of Step [C]is conducted by heating a Compound II with the imidazole derivative atabout 100 to about 200 C., more preferably at about 120 to about 150 C.

Under these conditions, the reaction proceeds smoothly regardless ofgeometric isomers of a Compound II.

The acid is exemplified by an organic acid such as acetic acid andpropionic acid and inorganic acid such as hydrochloric acid. The amountof the acid is generally from about 2 moles to a large excess moles permole of a Compound II.

Thus produced object Compound I is easily isolated and purified afterper se conventional means such as neutralization, filtration, extractionwith a suitable solvent (e.g. ethyl acetate, dichloromethane,chloroform).

As described in detail in the foregoing, by the method of the presentinvention, the compounds of the general Formula I useful as an effectivetranquilizer or hypnotic agents or as intermediates for other variouskinds of medicines can be produced in a high yield by simple procedures.

For further explanation of the present invention, the following examplesare given, wherein the word part(s) is based on weight unless otherwisenoted and the relationship between part(s) and volume part(s)corresponds to that between gram(s) and milliliter(s).

EXAMPLE Step (i) To a mixture of 40 volume parts of benzene and 2.42parts of Z-amino-S-nitrobenzophenone are added 9.64 parts of ethylorthobromoacetate and 3 parts of acetic acid, followed by heating underrefluxing for 7 hours. The reaction mixture is washed at first with asaturated aqueous sodium bicarbonate solution and then with water, driedover sodium sulfate and subjected to distillation under reducedpressure. This procedure gives2-(2-bromol-ethoxyethylideneamino)-5-nitrobenzophenone as an oilysubstance.

After a similar manner to the above, 2-(2-bromo-1-methoxyethylideneamino)-5-nitrobenzophenone (melting point: 90 to 91 C.)is obtained as pale yellow plates by employing methyl orthobromoacetateinstead of ethyl orthobromoacetate.

(ii) To a solution of 3.9 parts of2-(2-bromo-1-ethoxyethylideneamino)-5-nitrobenzophenone in 20 volumeparts of acetone is added a solution of 1.6 parts of sodium iodide in 15volume parts of acetone, followed by stirring at room temperature for 1hour.

The separated precipitates are removed off by filtration, and thefiltrate is concentrated under reduced pressure to give quantitatively2-(1-ethoxy-2-iodoethylideneamino)- S-nitrobenzophenone as an oilysubstance.

(i) To a solution of 1.95 parts of2-(2-bromo-1-ethoxyethylideneamino)-5-nitrobenzophenone in 25 volumeparts of dichloromethane is added 5 volume parts of liquid ammonia,followed by keeping at room temperature for 40 minutes. Thedichloromethane layer is washed with water, dried over sodium sulfateand subjected to distillation to remove the solvent. The residue iswashed with ethyl ether and then dried, whereby 2-an1ino-5-nitro-a-phenylbenzilideneaminoacetic acid ethyl ester is obtained asyellow crystals. Recrystallization from chloroform gives yellow prismsmelting at 163 to 164 C.

After a-similar manner to the above,2-amino-5-nitroa-phenylbenzilideneaminoacetic acid methyl ester isobtained as yellow prisms melting at 155 to 157 C. from 2 (2bromo-1-methoxyethyleneamino)-5-nitrobenzophenone.

(ii) To a solution of 2 parts of 2-(1-ethoxy-2-iodoethylideneamino)5-nitrobenzophenone in 50 volume parts of dichloromethane is added 20volume parts of liquid ammonia, and the mixture is stirred at roomtemperature for 1.5 hours. The dichloromethane layer is washed with asaturated aqueous sodium bicarbonate solution and water in this order,dried over sodium sulfate and then subjected to distillation to removethe solvent. The residue is washed with ethyl ether and dried to give2-amino-5-nitro-a-phenylbenzilideneaminoacetic acid ethyl ester asyellow crystals. Recrystallization from chloroform gives yellow prismsmelting at 163 to 164 C.

(iii) 2 amino-S-nitro-oa-phenylbenzilideneaminoacetic acid ethyl esterobtained in the above procedure is heated in xylene under reflux for 1.5hours, followed by subjecting to distillation under reduced pressure.The resulting crystals are recrystallized from ethyl ether to giveyellow needles melting at 136 to 137 C. Thus obtained needles areconsidered as the geometrical isomer of the starting ethyl ester.

(i) A mixture of 1.09 parts of2-amino-5-nitro-a-phenylbenzilideneaminoacetic acid ethyl ester meltingat 163 to 164 C., which is obtained in Step [B](i) or (ii), and 0.82part of Z-methylimidazole is heated at 140 C. for 45 minutes. Aftercooling, to the reaction mixture is added water, and the whole mixtureis extracted with ethyl acetate. The ethyl acetate layer is washed withwater, dried and subjected to distillation to remove the solvent. Theresidue is washed with ethyl alcohol, whereby 7-nitro- 5phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one is obtained as crystalsmelting at 222 to 223 C. Recrystallization from ethyl alcohol gives paleyellow flakes melting at 224 to 225 C.

(ii) A mixture of 1.09 parts of2-amino-5-nitro-a-phenylbenzilideneaminoacetic acid ethyl ester meltingat 136 to 137 C., which is produced in Step [B](iii), and 0.82 part of2-methylimidazole is heated at 140 C. for 40 minutes. After cooling, theresulting mixture is recrystallized from aqueous ethyl alcohol to give7-nitro-5-phenyl-1,3- dihydro 2H-1,4-benzodiazepin-2-one as yellowcrystals. Recrystallization from ethyl alcohol gives pale yellow flakesmelting at 224 to 225 C.

(iii) To a solution of 0.28 part of metallic sodium in 45 volume partsof methyl alcohol is added 3.13 parts of 2-amino-5-nitro-a-phenylbenzilideneaminoacetic acid methyl ester meltingat to 157 C., followed by stirring at room temperature for 20 minutes.After distillation of the solvent under reduced pressure, to the residueis added 30 volume parts of water. To the whole mixture is added 10weight percent hydrochloric acid until the pH value of the systembecomes 8.0, and the precipitates are filtered, washed with water anddried, whereby 7-nitro-5- phenyl 1,3 dihydro-ZH-1,4-benzodiazepin-2-oneis obtained as pale yellow crystals melting at 223 to 224 C.

After a similar manner to the above, 7-nitro-5-phenyl- 1,3dihydro-2H-1,4-benzodiazepin-2-one is obtained by employing sodiumethylate, and potassium methylate, re spectively, instead of sodiummethylate.

(iv) To a solution of 0.67 part of potassium hydroxide in 30 volumeparts of methyl alcohol is added 3.1 parts of 2amino-S-nitro-a-phenylbenzilideneaminoacetic acid methyl ester meltingat 155 to 157 0, followed by stirring at room temperature for 20minutes. The reaction mixture is subjected to distillation under reducedpressure, and to the residue is added 30 volume parts of water. To thewhole mixture is added 10 weight percent hydrochloric acid until the pHvalue of the system becomes 8.0, and the precipitates are filtered,washed with Water and dried, whereby7-nitro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-Z-one is obtained aspale yellow crystals melting at 223 to 224 C.

What is claimed is:

1. A method for the production of a compound of the formula:

H N N/ OgN- OgN

wherein Ph has the same meaning as above, with a compound of theformula:

XCH C(OR) (IV) wherein X represents a halogen atom and R representslower alkyl in the presence of a catalyst under heating to produce acompound of the formula:

(III) wherein Ph, R and X have the same meanings as above, (B) reactingthe thus-produced compound with liquid ammonia at a temperature aroundroom temperature to give a compound of the formula:

P 11 (II) wherein Ph and R have the same meaning as above and (C)subjecting the latter compound to a ring-closure reaction in thepresence of an acidic or basic compound.

2. A method according to claim 1 wherein reaction (B) is conducted inthe presence of a solvent and wherein the reaction proceeds underheating conditions at temperatures up to but not exceeding the boilingpoint of the solvent.

3. A method according to claim 1 wherein the compound XCH C(OR) in step(A) is used in molar excess of Compound V.

4. A method according to claim 1 wherein the catalyst used in step (A)is an inorganic or organic acid.

5. A method according to claim 4 wherein the catalyst is used in anexcess amount up to 8 moles per mole 0 Compound V.

6. A method according to claim 4 wherein the catalyst is selected fromthe group consisting of acetic acid, ptoluenesulfonic acid, hydrochloricacid and sulfuric acid.

7. A method according to claim 1 wherein at least one mole of XCH C(OR)is used per mole of Compound V.

8. A method according to claim 1 wherein an excess amount of liquidammonia is used in step (B).

9. A method according to claim 1 wherein the reaction in step (C)proceeds at room temperature or under heating conditions.

10. A method as claimed in claim 1, wherein the ringclosure reaction isconducted by treating a compound of the formula References Cited UNITEDSTATES PATENTS 6/1970 Schmitt 260239.3 D

HENRY R. JILES, Primary Examiner R. T. BOND, Assistant Examiner US. Cl.X.R.

